Molecule anticancer drugs development

Monastrol (Figure 10), the most representative Biginelli adduct in anticancer drug development, showed to be a cell permeable molecule whose mechanism of action on cancer cells involves the selective inhibition of kinesin Eg5 [63]. Kinesin Eg5 is a motor enzyme that is responsible for the formation and maintenance of mitotic spindles. The inhibition of this enzyme activity by monastrol leads to the loss of chromosome alignments and bipolar spindle formation. The resulting "monastral phenotype" inspired scientists to name this specific Biginelli compound as monastrol [63]. Fluorastrol (Figure 10), a monastrol-derived Eg5 inhibitor, showed to be more potent... 

The renaissance of the Biginelli MCR can be attributed to the obtained pyrimidine derivatives, which show remarkable pharmacological activity. A broad range of effects, including antiviral, antitumor, antibacterial, anti-inflammatory as well as antihypertensive activities has been ascribed to these partly reduced pyrimidine derivatives [96], such as 9-117 and 9-118 (antihypertensive agents) [97] and 9-119 (ala-adrenoceptor-selective antagonist) [98] (Scheme 9.24). Recently, the scope of this pharmacophore has been further increased by the identification of the 4-(3-hydroxyphenyl)-pyrimidin-2-thione derivative 9-120 known as monastrol [98], a novel cell-permeable lead molecule for the development of new anticancer drugs. Monastrol appears specifically to affect cell division (mitosis) by a new mechanism,... 

Combretastatins are a class of compounds originally derived from the African Willow tree (Combretum caffrum) and are powerful reversible inhibitors of tubulin polymerization. This class of molecules has been shown to bind to the colchicine binding site of tubulin, by the same mode of action as mentioned above (Sect. 1.2). Combretastatins consist of a ris-slilbcnc core structure. To date, there have been several compounds that have shown promise as potential anticancer drugs. However, development of these compounds as anticancer agents is limited by issues of chemical stability, bioavailibilty, toxicity, and solubility. 

The overexpression of GSTs in some cancer cells, particularly of GST Pl-1, offers an opportunity to detect and treat some cancer types (e.g., ovarian cancer). Recent developments in the design of small molecules that either inhibit the catalytic activity of GST Pl-1 or use GST Pl-1 catalytic site to release the actual anticancer agent, have shown promising results in preclinical studies, with the graduation of 66 and 96 as potential anticancer drug candidates currently undergoing clinical trials. 

Gelmon KA, Eisenhauer EA, Harris AL, et al. Anticancer Agents Targeting Signaling Molecules and Cancer Cell Environment Challenges for Drug Development J Natl Cancer Inst 1999 91 1281-1287. 

Nitrile groups can be introduced into molecules by reacting potassium cyanide with alkyl halides. The organic nitrile group has quite different properties associated with lethal inorganic cyanide Laetrile, for example, is extracted from apricot kernels, and was once developed as an anticancer drug. It was later proposed that the name be spelt liar-trial since the results of the clinical trials on laetrile turned out to have been falsified ... 

Nanoparticles were first developed around 1970 and are defined as solid colloidal particles, less then 1 pm in size, that consist of macromolecular compounds. They were initially devised as carriers for vaccines and anticancer drugs [11]. The use of nanoparticles for ophthalmic and oral delivery was also investigated [12]. Drugs or other biologically active molecules are dissolved, entrapped, or... 

Compound (53)was developed at Agouron through use of SBDD (125) and is under clinical investigation by Pfizer as an anticancer drug and as a treatment of proliferative retinopathy. Compound (54) is a stromelysin inhibitor discovered at Novartis (126), without explicit structural guidance. However, the lead molecule from which (54) was developed was originally obtained by X-ray structure-... 

The anticancer drugs delivered by liposomes include many small molecule drugs such as DOX, daunoru-bicin, platinates, taxanes, camptothecin, etc. The most successful development is DOX-encapsulated pegylated liposomes, with a trade name of Doxil in the U.S. market or Cylax in the European market. Doxil has shown significant clinical advantages over free DOX and conventional DOX liposomes.f Enhanced tumor accumulation of Doxil has been demonstrated in numerous preclinical studies over a variety of tumor models. Similar effects were also observed in clinical uses. 

K. A. Gelmon, E. A. Eisenhauer, A. L. Harris, M. J. Ratain, and P. Workman, Anticancer agents targeting signaling molecules and cancer cell environment challenges for drug development / Natl Cancer Inst 91 1281-1287 (1999). 

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